Hepatitis B is a common disease with a worldwide distribution. The virus is transmitted by blood and blood products, contamination of needles in IV drug abusers, sexually and vertically from infected or carrier mothers to infants. On a global basis, the disease is most common in Southeast Asia, Africa and parts of South America. In these areas, vertical transmission to infants at an early age results in a high proportion of infected individuals becoming chronic carriers of hepatitis B. Males acquiring hepatitis B as infants have approximately a 40% chance of dying from cirrhosis or primary hepatocellular carcinoma as a result of chronic hepatitis B infection. Females infected at birth have about a 15% chance of dying a similar death from chronic hepatitis B infection. It is estimated that there are 280,000,000 carriers of hepatitis B worldwide.
The field of antiviral chemotherapy is relatively new. Since the replication of viruses so intimately involves the host cell, it has been very difficult to identify viral specific sites for specific antiviral chemotherapy. Attempts to treat chronic carriers of hepatitis B have met with little success. Adenine arabinoside and inteferon have been used to treat chronic carriers. There have been three controlled studies comparing adenine arabinoside to a placebo in the treatment of chronic hepatitis B infection. In two of these studies, the response rate to adenine arabinoside was significantly better in treated patients than in controls (Bassendine et al, Gastroenterology, 80, 1016-1021, 1981; Yokosuta et al Gastroenterology, 89, 246-251, 1985). In a third controlled study, there was no significant benefit in the adenine arabinoside treated patients (Hoofnagle et al, Gastroenterology, 86, 150-157, 1984). Priming the patients with a tapering course of prednisone before therapy with adenine arabinoside has been reported to be beneficial (Perrillo, R. P. et al, Gastroenterology, 88, 780-786, 1985). However, in most open and controlled studies, only about 30% of treated patients show some benefit from therapy, and even these results are not very convincing. In addition, therapy with adenine arabinoside has been associated with bone marrow suppression, neuromuscular pain and neurotoxicity. Most trials of adenine arabinoside for the treatment of chronic hepatitis B infection have been discontinued because of the limited success and moderate toxicity with this antiviral agent. Attempts to treat chronic active hepatitis caused by hepatitis B virus with interferon alone or in combination with adenine arabinoside have also met with very limited success and considerable toxicity. Thus there is a lack of effective antiviral treatment for hepatitis B.
The 2',3'-dideoxynucleosides have been proposed as antiviral agents and, in fact, 2',3'-dideoxycytidine is being actively investigated as an antiviral agent for retroviruses including the human immunodeficiency viruses (HIV). Other 2',3'-dideoxynucleosides but not 2',3'-dideoxythymidine have been shown to be potent inhibitors of HIV (Mitsuya et al PNAS 82, 7096-7100, 1985; Mitsuya and Broder, PNAS 83, 1911-1915, 1986).
Burroughs Wellcome disclose in their published European patent application S.N. 8603662.0 that the dideoxynucleosides may be useful in the treatment of hepadnavirus infections like hepatitis B. However, they provide no experimental evidence to support this hypothesis and do not mention our unexpected finding that purine 2',3'-dideoxynucleosides are much more effective than pyrimidine 2',3'-dideoxynucleosides. Although 2',3'-dideoxynucleosides are known to have antiviral activity, the work disclosed has concentrated on this type of compound as being effective for retroviruses, specifically HIV. The most effective 2'3' dideoxynucleosides for HIV have been 2'3'-dideoxycytidine (ddC) and 2',3'-dideoxyadenosine (ddA), a pyrimidine 2',3'-dideoxynucleoside and a purine 2',3'-dideoxynucleoside, respectively. Obviously, it is impossible to predict the qualitative sensitivities of the hepadnaviruses to 2',3'-dideoxynucleosides based on known sensitivities of retroviruses to these compounds. This is not surprising since retroviruses are RNA viruses whereas hepadnaviruses are DNA viruses of a distinctly different family and replicate by a different mechanism.